Melatonin is secreted exclusively at night, and the duration of its secretion is proportional to the duration of night--longer in winter and shorter in summer. Animals use these seasonal changes in the duration of nocturnal melatonin secretion as a chemical signal to regulate the timing of seasonal changes in their behavior. Long nightly periods of secretion trigger winter-type behaviors, while short nightly periods of secretion trigger summer-type behaviors. In this project, we are testing the hypothesis that the seasonal melatonin signal (i.e., change in duration of its nightly secretion) is part of the mechanism that triggers winter depression in individuals who suffer from seasonal affective disorder (SAD). In animals, the melatonin response to seasonal change in nightlength has been shown to be mediated by a clearly defined neural circuit that originates in the retina and terminates in the pineal gland. The initial transduction of the photic signal appears to be mediated by novel opsins in the retina. The timing of melatonin secretion is programmed by circadian pacemaker cells in the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives retinal input and acts on the pineal via a multi-synaptic pathway. The SCN pacemaker appears to contain two components, one (E) that is synchronized with dusk and controls the evening onset of melatonin secretion and another (M) that is synchronized with dawn and controls the morning offset of melatonin secretion. Downstream responses to changes in duration of nocturnal melatonin secretion are mediated by G-protein-coupled melatonin-receptors in the pars tuberalis and elsewhere. To test the melatonin hypothesis of the pathogenesis of recurrent winter depression, we are carrying out a series of related studies. In the current project, 24-hour profiles of melatonin secretion are assessed twice, once in winter and once in summer, in patients with recurrent winter depression and in healthy controls matched for age, sex and menstrual status. For each melatonin assessment, individuals are admitted to a research unit and remain in a dark room for 24 hours while blood samples are obtained through an indwelling venous catheter. Plasma samples are subsequently be assayed for levels of melatonin. Our previous research has shown that the human retinohypothalamic-pineal axis has conserved a capacity to detect seasonal changes in the length of the night and to use this information to make proportional adjustments in the intrinsic duration of nocturnal melatonin secretion (the duration in constant dim light). The purpose of the present project is to determine whether and to what extent healthy volunteers and patients with SAD respond in this way to seasonal changes in the natural scotoperiod when they live in a modern urban environment in which they are exposed to ambient artificial light after dark. A failure of patients with SAD to exhibit seasonal changes in the duration of nocturnal melatonin secretion would indicate that the SCN is not registering seasonal changes in duration of the natural photoperiod and would falsify the classical melatonin hypothesis of pathogenesis of the disorder. One hundred and nineteen individuals have been studied. So far, results support the melatonin hypothesis of the pathogenesis of recurrent winter depression in men with seasonal affective disorder but not in women. In men with SAD, in contrast to healthy men, the intrinsic duration of nocturnal melatonin secretion is longer in winter than in summer, and this difference is highly statistically significant. This gender difference in our findings may be consistent with several other kinds of evidence indicating that mechanisms responsible for the pathogenesis of SAD may differ in men and women. A second, and unexpected finding was that most of the variance between winter and summer duration of nocturnal melatonin secretion can be attributed to winter-summer changes in the timing of morning offset of secretion, and not timing of onset of secretion. This finding may help to explain the now well-established clinical finding that morning light is more effective than evening light in the treatment of winter depression. It is also consistent with a recent finding that changes in the duration of the photoperiod to which rodents have been exposed selectively modifies electrical activity recorded in the SCN in vitro in the morning.